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Mechanisms underlying differences in systemic exposure of structurally similar active metabolites: comparison of two preclinical hepatic models.

ABSTRACT: Selection of in vitro models that accurately characterize metabolite systemic and hepatobiliary exposure remains a challenge in drug development. In the present study, mechanisms underlying differences in systemic exposure of two active metabolites, furamidine and 2,5-bis (5-amidino)-2-pyridyl furan (CPD-0801), were examined using two hepatic models from rats: isolated perfused livers (IPLs) and sandwich-cultured hepatocytes (SCH). Pafuramidine, a prodrug of furamidine, and 2,5-bis [5-(N-methoxyamidino)-2-pyridyl] furan (CPD-0868), a prodrug of CPD-0801, were selected for investigation because CPD-0801 exhibits greater systemic exposure than furamidine, despite remarkable structural similarity between these two active metabolites. In both IPLs and SCH, the extent of conversion of CPD-0868 to CPD-0801 was consistently higher than that of pafuramidine to furamidine over time (at most 2.5-fold); area under the curve (AUC) of CPD-0801 in IPL perfusate and SCH medium was at least 7-fold higher than that of furamidine. Pharmacokinetic modeling revealed that the rate constant for basolateral (liver to blood) net efflux (k(A_net efflux)) of total formed CPD-0801 (bound + unbound) was 6-fold higher than that of furamidine. Hepatic accumulation of both active metabolites was extensive (>95% of total formed); the hepatic unbound fraction (f(u,L)) of CPD-0801 was 5-fold higher than that of furamidine (1.6 versus 0.3%). Incorporation of f(u,L) into the pharmacokinetic model resulted in comparable k(A_net efflux,u) between furamidine and CPD-0801. In conclusion, intrahepatic binding markedly influenced the disposition of these active metabolites. A higher f(u,L) explained, in part, the enhanced perfusate AUC of CPD-0801 compared with furamidine in IPLs. SCH predicted the disposition of prodrug/metabolite in IPLs.

SUBMITTER: Yan GZ

PROVIDER: S-EPMC3083101 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature

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Mechanisms underlying differences in systemic exposure of structurally similar active metabolites: comparison of two preclinical hepatic models.

Yan Grace Zhixia GZ Brouwer Kim L R KL Pollack Gary M GM Wang Michael Zhuo MZ Tidwell Richard R RR Hall James E JE Paine Mary F MF

The Journal of pharmacology and experimental therapeutics 20110214 2

Selection of in vitro models that accurately characterize metabolite systemic and hepatobiliary exposure remains a challenge in drug development. In the present study, mechanisms underlying differences in systemic exposure of two active metabolites, furamidine and 2,5-bis (5-amidino)-2-pyridyl furan (CPD-0801), were examined using two hepatic models from rats: isolated perfused livers (IPLs) and sandwich-cultured hepatocytes (SCH). Pafuramidine, a prodrug of furamidine, and 2,5-bis [5-(N-methoxy ...[more]

PMID: 21320872

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Project description:Aberrant expression of CXCR4 has been indicated to play a role in the pathogenesis of systemic lupus erythematosus (SLE), but the mechanism of CXCR4 dysregulation in SLE is unclear. This study is aimed to explore the clinical significance and possible mechanisms of abnormal CXCR4 expression on B cells from patients with untreated SLE. Expression of CXCR4 on peripheral B cells was determined by flow cytometry and western blotting. Freshly isolated B cells were cultured with exogenous interleukin 21(IL-21) in the presence or absence of CD40 ligand (CD40L) plus anti-IgM antibody (aIgM), and changes in CXCR4 expression were detected. Involvement of phosphatidylinositol 3 kinase (PI3K)/Akt and Janus kinase/Signal transducer and activator of transcription (JAK/STAT) signaling pathways was assessed by adding blocking agents Ly294002 and AG490. Since CD63 is reported to mediate endosomal recruitment of CXCR4 and BCL6 is capable of silencing CD63 gene transcription, we also measured BCL6 and CD63 gene transcription with real-time PCR. It was shown that CXCR4 expression on B cells was significantly upregulated in SLE patients, especially in those with lupus nephritis, and was positively correlated with SLE Disease Activity Index scores and negatively with the serum complement 3 levels (P<0.05). Downregulation of CXCR4 by IL-21 was intact. In contrast, a similar effect of aIgM plus CD40L in downregulating CXCR4 expression was defective in SLE patients but was restored by co-stimulation with IL-21 in vitro. Both Ly294002 and AG490 promoted downregulation of surface CXCR4 expression on B cells from SLE patients (P=0.078 and P=0.064). Furthermore, B cells from SLE patients exhibited diminished CD63 mRNA and enhanced BCL6 mRNA expression (both P<0.05). To sum up, CXCR4 was overexpressed on SLE B cells, positively correlating with disease activity and kidney involvement. Overactivation of the PI3K/Akt and JAK/STAT pathways as well as defective CD63 synthesis may contribute to CXCR4 dysregulation in SLE.

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Mechanisms underlying differences in systemic exposure of structurally similar active metabolites: comparison of two preclinical hepatic models.

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Mechanisms underlying differences in systemic exposure of structurally similar active metabolites: comparison of two preclinical hepatic models.

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